Monitoring of Unfractionated Heparin in Severe COVID-19: An Observational Study of Patients on CRRT and ECMO

Abstract

Objective Severe cases of coronavirus disease 2019 (COVID-19) can require continuous renal replacement therapy (CRRT) and/or extracorporeal membrane oxygenation (ECMO). Unfractionated heparin (UFH) to prevent circuit clotting is mandatory but monitoring is complicated by (pseudo)-heparin resistance. In this observational study, we compared two different activated partial thromboplastin time (aPTT) assays and a chromogenic anti-Xa assay in COVID-19 patients on CRRT or ECMO in relation to their UFH dosages and acute phase reactants. Materials and Methods The aPTT (optical [aPTT-CS] and/or mechanical [aPTT-STA] clot detection methods were used), anti-Xa, factor VIII (FVIII), antithrombin III (ATIII), and fibrinogen were measured in 342 samples from 7 COVID-19 patients on CRRT or ECMO during their UFH treatment. Dosage of UFH was primarily based on the aPTT-CS with a heparin therapeutic range (HTR) of 50–80s. Associations between different variables were made using linear regression and Bland–Altman analysis. Results Dosage of UFH was above 35,000IU/24 hours in all patients. aPTT-CS and aPTT-STA were predominantly within the HTR. Anti-Xa was predominantly above the HTR (0.3–0.7 IU/mL) and ATIII concentration was >70% for all patients; mean FVIII and fibrinogen were 606% and 7.5 g/L, respectively. aPTT-CS correlated with aPTT-STA (r 2 = 0.68) with a bias of 39.3%. Correlation between aPTT and anti-Xa was better for aPTT-CS (0.78 ≤ r 2 ≤ 0.94) than for aPTT-STA (0.34 ≤ r 2 ≤ 0.81). There was no general correlation between the aPTT-CS and ATIII, FVIII, fibrinogen, thrombocytes, C-reactive protein, or ferritin. Conclusion All included COVID-19 patients on CRRT or ECMO conformed to the definition of heparin resistance. A patient-specific association was found between aPTT and anti-Xa. This association could not be explained by FVIII or fibrinogen.

Serial EXTEM, FIBTEM, and tPA Rotational Thromboelastometry Observations in the Maastricht Intensive Care COVID Cohort—Persistence of Hypercoagulability and Hypofibrinolysis Despite Anticoagulation

“…Anti-Xa activity was determined using an LMWH calibration line (aXa-LMWH; Hyphen Biomed). UFH activity was subsequently calculated with a previously determined formula: UFH anti-Xa = 1.55 * LMWH anti-Xa ( 26 ). Bilirubin (Bilirubin Total, third-generation; Roche Diagnostics, Basel, Switzerland) and creatinine (Enzymatic Reagent; Roche Diagnostics) were determined in serum on a COBAS® 8000 (Roche Diagnostics).…”

Extracorporeal Membrane Oxygenation Induces Early Alterations in Coagulation and Fibrinolysis Profiles in COVID-19 Patients with Acute Respiratory Distress Syndrome

“…12,13 Some authors suggested that these bleeding events might result from worsening COVID-19-associated coagulopathy during ECMO support, further leading to disseminated intravascular coagulation, enhanced fibrinolysis or acquired von Willebrand syndrome, or from heparin overdose. 14 However, data on the kinetics of coagulation and fibrinolysis markers over the course of vv-ECMO in COVID-19 patients which might support this hypothesis are scarce [15][16][17][18][19] and direct comparisons with non-COVID-19 patients are lacking.…”

Suggestions for global coagulation assays for the assessment of COVID-19 associated hypercoagulability

“…Anti-Xa (aXa) test samples were diluted (1 unit sample: 2 units pooled reference plasma) and determined using a LMWH calibration line (Biophen LMWH calibrator; Hyphen Biomed). For UFH a previously determined correction factor was applied: aXa-UFH = 1.55 ∗ aXa-LMWH [ 18 ].…”